Intermittent neural stimulation with physiologic response monitor

ABSTRACT

Various aspects of the present subject matter provide an implantable medical device. In various embodiments, the device comprises a pulse generator, a first monitor and a controller. The pulse generator is adapted to generate a neural stimulation signal for a neural stimulation therapy. The neural stimulation signal has at least one adjustable parameter. The first monitor is adapted to detect an undesired effect. In some embodiments, the undesired effect is myocardial infarction. The controller is adapted to respond to the first monitor and automatically adjust the at least one adjustable parameter of the neural stimulation signal to avoid the undesired effect of the neural stimulation therapy. Other aspects are provided herein.

CLAIM OF PRIORITY

This application is a continuation of and claims the benefit of priorityunder 35 U.S.C. § 120 to U.S. patent application Ser. No. 15/485,684,filed on Apr. 12, 2017, which is a continuation of and claims thebenefit of priority under 35 U.S.C. § 120 to U.S. patent applicationSer. No. 14/218,092, filed on Mar. 18, 2014, now issued as U.S. Pat. No.9,623,255, which is a continuation of and claims the benefit of priorityunder 35 U.S.C. § 120 to U.S. patent application Ser. No. 13/396,405,filed on Feb. 14, 2012, now issued as U.S. Pat. No. 8,682,434, which isa division of and claims the benefit of priority under 35 U.S.C. § 120to U.S. patent application Ser. No. 11/000,249, filed on Nov. 30, 2004,now issued as U.S. Pat. No. 8,126,559, each of which is herebyincorporated by reference herein in its entirety.

CROSS REFERENCE TO RELATED APPLICATIONS

The following commonly assigned U.S. patent application is related, andis incorporated by reference herein in its entirety: “Sensing WithCompensation for Neural Stimulator,” U.S. patent application Ser. No.10/746,847, filed on Dec. 24, 2003; and “System and Method for FilteringNeural Stimulation,” U.S. patent application Ser. No. 10/982,001, filedNov. 4, 2004, now issued as U.S. Pat. No. 8,200,331.

TECHNICAL FIELD

This application relates generally to neural stimulation and, moreparticularly, to systems, devices and methods to automatically avoid orprevent inappropriate neural stimulation.

BACKGROUND

Centrally mediated reflex pathways modulate cardiac rate, contractility,and excitability. Baroreceptors and chemoreceptors in the heart, greatvessels, and lungs, transmit cardiac activity through vagal andsympathetic afferent fibers to the central nervous system. Activation ofsympathetic afferents triggers reflex sympathetic activation,parasympathetic inhibition, vasoconstriction, and tachycardia. Incontrast, parasympathetic activation results in bradycardia,vasodilation, and inhibition of vasopressin release.

Some neural stimulators treat a variety of disorders, such as epilepsy,obesity, and breathing disorders. Modulation of the sympathetic andparasympathetic nervous system with neural stimulation has been shown tohave positive clinical benefits, such as protecting the myocardium fromfurther remodeling and predisposition to fatal arrhythmias following amyocardial infarction. Experimentally, neural stimulation has been shownto have a significant effect on several cardiovascular conditions, andmay be used to treat hypertension, post-Ml remodeling, and heartfailure.

However, neural stimulation may have undesired results. For example,neural stimulation in the vicinity of the heart may inadvertentlystimulate the myocardium, altering intrinsic rate and activationsequence. That is, neural stimulation in the vicinity of the heart mayhave sufficient voltage and pulse width to capture the surroundingmyocardium, resulting in unintended atrial or ventriculardepolarization. Other potential undesired results include inappropriatestimulation of other nerves than the target nerve, and inappropriatestimulation of smooth muscle proximate to the target nerve.

SUMMARY

Various embodiments provide an implantable medical device, comprising apulse generator, a first monitor and a controller. The pulse generatoris adapted to generate a neural stimulation signal for a neuralstimulation therapy. The neural stimulation signal has at least oneadjustable parameter. The first monitor is adapted to detect anundesired effect. The controller is adapted to respond to the firstmonitor and automatically adjust the at least one adjustable parameterof the neural stimulation signal to avoid the undesired effect of theneural stimulation therapy.

Various embodiments provide an implantable device, comprising a neuralstimulator, a first monitor, a second monitor, and a controller. Theneural stimulator includes a pulse generator to generate a neuralstimulation signal for a neural stimulation therapy, and a modulator toadjust at least one stimulation parameter of the neural stimulationsignal. The first monitor is adapted to monitor at least one feedbackparameter and provide a first signal indicative of the parameter duringthe neural stimulation therapy and a second signal indicative of thefeedback parameter without the neural stimulation. The second monitor isadapted to monitor myocardial capture from the neural stimulationtherapy and provide a third signal indicative of a detected myocardialcapture. The controller is adapted to respond to the first, second andthird signals, determine a detected change for the at least onestimulation parameter based on the first and second signals, and providea therapy control signal to the modulator based on the third signal andthe detected change to achieve a desired change for the at least onestimulation parameter while avoiding myocardial capture.

Various embodiments provide a method, comprising applying neuralstimulation therapy to at least one targeted nerve, including generatinga neural stimulation signal for use to provide the neural stimulationtherapy, and further comprising monitoring a patient for an undesiredresponse to the neural stimulation signal, and automatically adjustingat least one parameter of the neural stimulation signal to avoid theundesired response to the neural stimulation signal.

Various embodiments provide a method, comprising applying neuralstimulation therapy to at least one targeted nerve, including generatinga neural stimulation signal for use to provide the neural stimulationtherapy, and further comprising monitoring a patient for both a desiredresponse and an undesired response to the neural stimulation signal, andautomatically adjusting at least one parameter of the neural stimulationsignal to achieve the desired response and avoid the undesired responseto the neural stimulation signal.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects will be apparent to persons skilled in the art upon reading andunderstanding the following detailed description and viewing thedrawings that form a part thereof, each of which are not to be taken ina limiting sense. The scope of the present invention is defined by theappended claims and their equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B illustrate neural mechanisms for peripheral vascularcontrol.

FIGS. 2A-2C illustrate a heart.

FIG. 3 illustrates baroreceptors in the area of the carotid sinus,aortic arch and pulmonary artery.

FIG. 4 illustrates baroreceptors in and around a pulmonary artery.

FIG. 5 illustrates baroreceptor fields in the aortic arch, near theligamentum arteriosum and the trunk of the pulmonary artery.

FIG. 6 illustrates a system including an implantable medical device(IMD) and a programmer, according to various embodiments of the presentsubject matter.

FIG. 7 illustrates an implantable medical device (IMD) such as the IMDshown in the system of FIG. 6, according to various embodiments of thepresent subject matter.

FIG. 8 illustrates a system including a programmer, an implantableneural stimulator (NS) device and an implantable cardiac rhythmmanagement (CRM) device, according to various embodiments of the presentsubject matter.

FIG. 9 illustrates an implantable neural stimulator (NS) device such asshown in the system of FIG. 8, according to various embodiments of thepresent subject matter.

FIG. 10 illustrates an implantable cardiac rhythm management (CRM)device such as shown in the system of FIG. 8, according to variousembodiments of the present subject matter.

FIG. 11 illustrates a system to automatically adjust a neuralstimulation signal to achieve a desired result and avoid an undesiredresult, according to various embodiments.

FIG. 12 illustrates an application, illustrated as functional blockdiagrams for a system, to modulate neural stimulation, according tovarious embodiments of the present subject matter.

FIG. 13 illustrates a neural stimulation application, according tovarious embodiments.

FIG. 14 illustrates a neural stimulation application, according tovarious embodiments.

FIG. 15 is a graphical illustration of the relationship between a changein blood pressure and a rate of a stimulation signal.

FIG. 16 illustrates a method to detect myocardial capture, according tovarious embodiments.

FIG. 17 illustrates a method to detect myocardial capture, according tovarious embodiments.

FIG. 18 illustrates a method to detect myocardial capture, according tovarious embodiments.

DETAILED DESCRIPTION

The following detailed description of the present subject matter refersto the accompanying drawings which show, by way of illustration,specific aspects and embodiments in which the present subject matter maybe practiced. These embodiments are described in sufficient detail toenable those skilled in the art to practice the present subject matter.Other embodiments may be utilized and structural, logical, andelectrical changes may be made without departing from the scope of thepresent subject matter. References to “an”, “one”, or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.The following detailed description is, therefore, not to be taken in alimiting sense, and the scope is defined only by the appended claims,along with the full scope of legal equivalents to which such claims areentitled.

This disclosure describes a neural stimulation device with the abilityto detect undesired results of neural stimulation, such as thestimulation of an unintended region, and adjust neural stimulationparameters to avoid the undesired results. Some device embodimentsstimulate a target nerve or nerves and avoid inappropriate stimulationand capture of the myocardia; some device embodiments stimulate a targetnerve or nerves, and avoid inappropriate stimulation of smooth muscleproximate to the target nerve(s); and some device embodiments stimulatea target nerve or nerves, and avoid inappropriate stimulation of othernerves proximate to the target nerve(s).

Examples of inappropriate stimulation of a smooth muscle includestimulating a pectoral muscle and stimulating a diaphragm, which cancause undesired contractions or twitching in these muscles. Examples ofinappropriate stimulation of other nerves include stimulation oflaryngeal nerve, resulting in undesired coughing, and stimulation of thephrenic nerve, resulting in undesired hiccups, when the desiredstimulation targets an afferent nerve such as the vagus nerve tostimulate the parasympathetic response.

A problem is neural stimulation in the vicinity of the heart (e.g. fatpads, great vessels, etc.) may have sufficient voltage/pulse width tocapture the myocardium, and elicit atrial or ventricular depolarization.A solution is to apply an autocapture algorithm in the neuralstimulation lead or other sensing leads to verify the absence ofcapture. If no capture, the stimulation is okay. If there is capture,the neural stimulation is adjusted to avoid capture. Some deviceembodiments to avoid inappropriate myocardial capture are able to detectmyocardial activation, and automatically adjust stimulation above thenerve activation threshold and below the myocardial activationthreshold. In various embodiments, the device monitors changes inphysiological parameters to verify the presence of appropriatestimulation of the target nerve(s). Thus, the device adjusts neuralstimulation parameters such as amplitude, frequency, etc. to insureneural activation and prevent myocardial activation.

A neural stimulation lead is placed in an appropriate location toprovide neural stimulation therapy. For example, various embodimentsprovide an expandable stimulation lead placed in the pulmonary artery inthe proximity of a high concentration of baroreceptors. Variousembodiments provide a transvascular lead placed proximal to one of thecardiac fat pads, various embodiments provide an epicardial lead placedin the cardiac fat pad, various embodiments provide a cuff electrodeplaced around a nerve trunk, such as the aortic nerve, carotid nerve, orvagus nerve, and various embodiments provide a transvascular lead placedproximal to a nerve trunk.

A neural stimulation lead is connected to an implantable pulsegenerator, which delivers intermittent neural stimulation therapythrough the lead to target nerve(s). Some device embodiments detect thepresence of an inappropriate stimulation, such as myocardial activation,after each stimulation burst. In neural stimulation devices to avoidmyocardial capture, some device embodiments detect electrical activityat the neural stimulation lead after a blanking period; and some deviceembodiments detect electrical activity at one or more distal leads,finding myocardial activation if sufficiently high electrical activityis sensed at the neural stimulation lead as compared to the distal lead.If the neural stimulation burst is too long and depolarization is maskedby the stimulation burst, some device embodiments periodically test formyocardial activation using a short burst of neural stimulation to allowthe device to accurately perform the detection algorithm.

If myocardial activation is detected, the neural stimulation devicegradually reduces the intensity of neural stimulation by appropriatelyadjusting one or more parameters of the neural stimulation signal.Examples of adjustable parameters include but are not limited toamplitude, frequency, and pulse width. Detection and adjustment isrepeated until the absence of myocardial activation is verified. Invarious embodiments, the device confirms the presence of neuralstimulation after the absence of myocardial activation is confirmed. Insome embodiments, the device monitors one or more physiologicalparameters such as heart rate, blood pressure and the like, immediatelybefore and either during or immediately after a period of neuralstimulation. Neural activation is detected if the physiologicalparameters are affected by a sufficient percentage in the expecteddirection. Some embodiments use the neural stimulation lead to recordneural activity before and after a period of neural stimulation, anddetect the presence of neural activation based on the response of thenerve traffic.

Various embodiments provide a programmable neurostimulation device withauto-threshold auto-capture features. In some device embodiments, thefunctional effect of the neurostimulation is programmed, and the deviceis adapted to automatically adjust stimulation parameters to achieve theprogrammed function while avoiding unwanted side effects like myocardialstimulation, neural stimulation of non-targeted nerves, and smoothmuscle stimulation. An example of a programmed function effect of neuralstimulation is to change a heart rate by a quantitative number or apercentage.

Provided below is a discussion of the autonomic nervous system,embodiments of systems/devices to provide neural stimulation withavoidance of inappropriate stimulation or undesired results, andembodiments of programmed therapy applications capable of being providedby the illustrated systems.

Autonomic Nervous System (ANS)

The automatic nervous system (ANS) regulates “involuntary” organs, whilethe contraction of voluntary (skeletal) muscles is controlled by somaticmotor nerves. Examples of involuntary organs include respiratory anddigestive organs, and also include blood vessels and the heart. Often,the ANS functions in an involuntary, reflexive manner to regulateglands, to regulate muscles in the skin, eye, stomach, intestines andbladder, and to regulate cardiac muscle and the muscle around bloodvessels, for example.

The ANS includes, but is not limited to, the sympathetic nervous systemand the parasympathetic nervous system. The sympathetic nervous systemis affiliated with stress and the “fight or flight response” toemergencies. Among other effects, the “fight or flight response”increases blood pressure and heart rate to increase skeletal muscleblood flow, and decreases digestion to provide the energy for “fightingor fleeing.” The parasympathetic nervous system is affiliated withrelaxation and the “rest and digest response” which, among othereffects, decreases blood pressure and heart rate, and increasesdigestion to conserve energy. The ANS maintains normal internal functionand works with the somatic nervous system.

Some neural stimulation affects the heart rate, blood pressure,vasodilation and vasoconstriction. The heart rate and force is increasedwhen the sympathetic nervous system is stimulated, and is decreased whenthe sympathetic nervous system is inhibited (the parasympathetic nervoussystem is stimulated).

Baroreflex is a reflex triggered by stimulation of a baroreceptor. Abaroreceptor includes any sensor of pressure changes, such as sensorynerve endings in the wall of the auricles of the heart, vena cava,aortic arch and carotid sinus, that is sensitive to stretching of thewall resulting from increased pressure from within, and that functionsas the receptor of the central reflex mechanism that tends to reducethat pressure. Clusters of nerve cells, such as within a cardiac fatpad, can be referred to as autonomic ganglia. These nerve cells can alsobe electrically stimulated to induce a baroreflex, which inhibits thesympathetic nerve activity and stimulates parasympathetic nerveactivity. Autonomic ganglia thus forms part of a baroreflex pathway.Afferent nerve trunks, such as the vagus, aortic and carotid nerves,leading from the sensory nerve endings also form part of a baroreflexpathway. Stimulating a baroreflex pathway and/or baroreceptors inhibitssympathetic nerve activity (stimulates the parasympathetic nervoussystem) and reduces systemic arterial pressure by decreasing peripheralvascular resistance and cardiac contractility. Baroreceptors arenaturally stimulated by internal pressure and the stretching of vesselwall (e.g. arterial wall).

Baroreflex functions as a negative feedback system, and relates to areflex mechanism triggered by stimulation of a baroreceptor or someafferent nerves. Increased pressure stretches blood vessels, which inturn activates baroreceptors in the vessel walls. Activation ofbaroreceptors naturally occurs through internal pressure and stretchingof the arterial wall, causing baroreflex inhibition of sympathetic nerveactivity (SNA) and a reduction in systemic arterial pressure. Anincrease in baroreceptor activity induces a reduction of SNA, whichreduces blood pressure by decreasing peripheral vascular resistance.FIGS. 1A and 1B illustrate neural mechanisms for peripheral vascularcontrol. FIG. 1A generally illustrates afferent nerves to vasomotorcenters. An afferent nerve conveys impulses toward a nerve center. Avasomotor center relates to nerves that dilate and constrict bloodvessels to control the size of the blood vessels. FIG. 1B generallyillustrates efferent nerves from vasomotor centers. An efferent nerveconveys impulses away from a nerve center.

Stimulating the sympathetic and parasympathetic nervous systems can haveeffects other than heart rate and blood pressure. For example,stimulating the sympathetic nervous system dilates the pupil, reducessaliva and mucus production, relaxes the bronchial muscle, reduces thesuccessive waves of involuntary contraction (peristalsis) of the stomachand the motility of the stomach, increases the conversion of glycogen toglucose by the liver, decreases urine secretion by the kidneys, andrelaxes the wall and closes the sphincter of the bladder. Stimulatingthe parasympathetic nervous system (inhibiting the sympathetic nervoussystem) constricts the pupil, increases saliva and mucus production,contracts the bronchial muscle, increases secretions and motility in thestomach and large intestine, and increases digestion in the smallintention, increases urine secretion, and contracts the wall and relaxesthe sphincter of the bladder. The functions associated with thesympathetic and parasympathetic nervous systems are many and can becomplexly integrated with each other. Thus, an indiscriminatestimulation of the sympathetic and/or parasympathetic nervous systems toachieve a desired response, such as vasodilation, in one physiologicalsystem may also result in an undesired response in other physiologicalsystems. Additionally, neural stimulation of a non-targeted nerve alongwith a targeted nerve can also result in undesired responses.

Some aspects of the present subject matter locally stimulate specificnerve endings in arterial walls rather than stimulate afferent nervetrunks in an effort to stimulate a desire response (e.g. reducedhypertension) while reducing the undesired effects of indiscriminatestimulation of the nervous system. For example, some embodimentsstimulate baroreceptor sites in the pulmonary artery. Some embodimentsof the present subject matter involve stimulating baroreceptor sites ornerve endings in the aorta, the chambers of the heart, the fat pads ofthe heart, and some embodiments of the present subject matter involvestimulating an afferent nerve trunk, such as the vagus, carotid andaortic nerves. Some embodiments stimulate afferent nerve trunks using acuff electrode, and some embodiments stimulate afferent nerve trunksusing an intravascular lead positioned in a blood vessel proximate tothe nerve, such that the electrical stimulation passes through thevessel wall to stimulate the afferent nerve trunk.

FIGS. 2A-2C illustrate a heart. As illustrated in FIG. 2A, the heart 201includes a superior vena cava 202, an aortic arch 203, and a pulmonaryartery 204, and is useful to provide a contextual relationship with theillustrations in FIGS. 3-5. As is discussed in more detail below, thepulmonary artery 204 includes baroreceptors. A lead is capable of beingintravascularly inserted through a peripheral vein and through thetricuspid valve into the right ventricle of the heart (not expresslyshown in the figure) similar to a cardiac pacemaker lead, and continuefrom the right ventricle through the pulmonary valve into the pulmonaryartery. A portion of the pulmonary artery and aorta are proximate toeach other. Various embodiments stimulate baroreceptors in the aortausing a lead intravascularly positioned in the pulmonary artery. Thus,according to various aspects of the present subject matter, thebaroreflex is stimulated in or around the pulmonary artery by at leastone electrode intravascularly inserted into the pulmonary artery. Invarious embodiments, a wireless stimulating device, with or withoutpressure sensing capability, may be positioned via catheter into thepulmonary artery. Control of stimulation and/or energy for stimulationmay be supplied by another implantable or external device viaultrasonic, electromagnetic or a combination thereof. Aspects of thepresent subject matter provide a relatively noninvasive surgicaltechnique to implant a baroreceptor stimulator intravascularly into thepulmonary artery.

FIGS. 2B-2C illustrate the right side and left side of the heart,respectively, and further illustrate cardiac fat pads which have gangliaor nerve endings that function as baroreceptor sites. FIG. 2Billustrates the right atrium 205, right ventricle 206, sinoatrial node207, superior vena cava 202, inferior vena cava 208, aorta 209, rightpulmonary veins 210, and right pulmonary artery 211. FIG. 2B alsoillustrates a cardiac fat pad 212 between the superior vena cava andaorta. Baroreceptor nerve endings in the cardiac fat pad 212 arestimulated in some embodiments using an electrode screwed or otherwiseinserted into the fat pad, and are stimulated in some embodiments usingan intravenously-fed lead proximately positioned to the fat pad in avessel such as the right pulmonary artery or superior vena cava, forexample. FIG. 2C illustrates the left atrium 213, left ventricle 214,right atrium 205, right ventricle 206, superior vena cava 202, inferiorvena cava 208, aorta 209, right pulmonary veins 210, left pulmonary vein215, right pulmonary artery 211, and coronary sinus 216. FIG. 2C alsoillustrates a cardiac fat pad 217 located proximate to the right cardiacveins and a cardiac fat pad 218 located proximate to the inferior venacava and left atrium. Baroreceptor nerve endings in the fat pad 217 arestimulated in some embodiments using an electrode screwed or otherwiseinserted into the fat pad 217, and are stimulated in some embodimentsusing an intravenously-fed lead proximately positioned to the fat pad ina vessel such as the right pulmonary artery 211 or right pulmonary vein210, for example. Baroreceptors in the cardiac fat pad 218 arestimulated in some embodiments using an electrode screwed or otherwiseinserted into the fat pad, and are stimulated in some embodiments usingan intravenously-fed lead proximately positioned to the fat pad in avessel such as the inferior vena cava 208 or coronary sinus or a lead inthe left atrium 213, for example.

FIG. 3 illustrates baroreceptors in the area of the carotid sinus 319,aortic arch 303 and pulmonary artery 304. The aortic arch 303 andpulmonary artery 304 were previously illustrated at 203 and 204 withrespect to the heart in FIG. 2A. As illustrated in FIG. 3, the vagusnerve 320 extends and provides sensory nerve endings 321 that functionas baroreceptors in the aortic arch 303, in the carotid sinus 319 and inthe common carotid artery 322. The glossopharyngeal nerve 323 providesnerve endings 324 that function as baroreceptors in the carotid sinus319. These nerve endings 321 and 324, for example, are sensitive tostretching of the wall resulting from increased pressure from within.Activation of these nerve endings reduce pressure. Although notillustrated in the figures, the fat pads and the atrial and ventricularchambers of the heart also include baroreceptors. Cuffs have been placedaround afferent nerve trunks, such as the vagal nerve, leading frombaroreceptors to vasomotor centers to stimulate the baroreflex.According to various embodiments of the present subject matter, afferentnerve trunks can be stimulated using a cuff or intravascularly-fed leadpositioned in a blood vessel proximate to the afferent nerves.

FIG. 4 illustrates baroreceptors in and around a pulmonary artery 404.The superior vena cava 402 and the aortic arch 403 are also illustrated.As illustrated, the pulmonary artery 404 includes a number ofbaroreceptors 425. Furthermore, a cluster of closely spacedbaroreceptors 426 is situated near the attachment of the ligamentumarteriosum. FIG. 4 also illustrates the right ventricle 406 of theheart, and the pulmonary valve 427 separating the right ventricle 406from the pulmonary artery 404. According to various embodiments of thepresent subject matter, a lead is inserted through a peripheral vein andthreaded through the tricuspid valve into the right ventricle, and fromthe right ventricle 406 through the pulmonary valve 427 and into thepulmonary artery 404 to stimulate baroreceptors in and/or around thepulmonary artery. In various embodiments, for example, the lead ispositioned to stimulate the cluster of baroreceptors 426 near theligamentum arteriosum. FIG. 5 illustrates baroreceptor fields 526 in theaortic arch 503, near the ligamentum arteriosum and the trunk of thepulmonary artery 504. Some embodiments position the lead in thepulmonary artery to stimulate baroreceptor sites in the aorta and/or fatpads, such as are illustrated in FIGS. 2B-2C.

Systems to Provide Neural Stimulation with Avoidance of InappropriateStimulation

Various embodiments of the present subject matter include stand-aloneimplantable neural stimulator (NS) systems, include implantable devicesthat have integrated NS and cardiac rhythm management (CRM) components,and include systems with at least one implantable NS device and animplantable CRM device capable of communicating with each other eitherwirelessly or through a wire lead connecting the implantable devices.Examples of neural stimulators include anti-hypertension (AHT) devicesor AHT components that are used to treat hypertension. Examples ofimplantable cardiac rhythm management (CRM) devices include pacemakers,implantable cardiac defibrillators (ICDs), and implantable devicescapable of performing pacing and defibrillating functions. ImplantableCRM devices provide electrical stimulation to selected chambers of theheart in order to treat disorders of cardiac rhythm. An implantablepacemaker, for example, is a CRM device that paces the heart with timedpacing pulses. The pacing pulses can be timed from other pacing pulsesor sensed electrical activity. If functioning properly, the pacemakermakes up for the heart's inability to pace itself at an appropriaterhythm in order to meet metabolic demand by enforcing a minimum heartrate. Some CRM devices synchronize pacing pulses delivered to differentareas of the heart in order to coordinate the contractions. Coordinatedcontractions allow the heart to pump efficiently while providingsufficient cardiac output. Although implantable systems are illustratedand discussed, various aspects and embodiments of the present subjectmatter can be implemented in external devices. Integrating NS and CRMfunctions that are either performed in the same or separate devicesimproves aspects of the NS therapy and cardiac therapy by allowing thesetherapies to work together intelligently.

FIG. 6 illustrates a system 628 including an implantable medical device(IMD) 629 and a programmer 630, according to various embodiments of thepresent subject matter. Various embodiments of the IMD 629 includeneural stimulator functions only, and various embodiments include acombination of NS and CRM functions. The programmer 630 and the IMD 629are capable of wirelessly communicating data and instructions. Invarious embodiments, for example, the programmer 630 and IMD 629 usetelemetry coils to wirelessly communicate data and instructions. Thus,the programmer can be used to adjust the programmed therapy provided bythe IMD 629, and the IMD can report device data (such as battery andlead resistance) and therapy data (such as messages and sense andstimulation data) to the programmer using radio telemetry, for example.

FIG. 7 illustrates an implantable medical device (IMD) 729 such as theIMD 629 shown in the system of FIG. 6, according to various embodimentsof the present subject matter. The illustrated IMD 729 performs NSfunctions, and includes controller circuitry 730 and a memory 731. Thecontroller circuitry 730 is capable of being implemented using hardware,software, and combinations of hardware and software. For example,according to various embodiments, the controller circuitry 730 includesa processor to perform instructions embedded in the memory 731 toperform functions associated with NS therapy such as AHT therapy. Forexample, the illustrated device 729 further includes a transceiver 732and associated circuitry for use to communicate with a programmer oranother external or internal device. Various embodiments have wirelesscommunication capabilities. For example, some transceiver embodimentsuse a telemetry coil to wirelessly communicate with a programmer oranother external or internal device.

The illustrated device 729 further includes neural stimulation circuitry733. Various embodiments of the device also includes sensor circuitry734 used to monitor physiology parameters such as heart rate, forexample. One or more leads are able to be connected to the sensorcircuitry and neural stimulation circuitry. The neural stimulationcircuitry is used to apply electrical stimulation pulses to desiredtarget nerve(s), such as baroreceptor sites in the pulmonary artery,through one or more stimulation electrodes. The sensor circuitry is usedto detect undesired responses, and in some embodiments insure desiredresponses, of the neural stimulation. Some embodiments provide sensorcircuitry to detect myocardial capture, some embodiments provide sensorcircuitry to detect capture of smooth muscle, and some embodimentsprovide sensor circuitry to detect neural activity in an non-targetednerve. In some embodiments, the sensor circuitry is used to detect andprocess ANS nerve activity and/or surrogate parameters such as heartrate, blood pressure, respiration and the like, to determine the ANSactivity.

According to various embodiments, the stimulation circuitry includesmodules to set any one or any combination of two or more of thefollowing pulse features: the amplitude of the stimulation pulse, thefrequency of the stimulation pulse, the burst frequency, pulse width andduty cycle of a stimulation pulse, and the wave morphology of the pulse.Examples of wave morphology include a square wave, triangle wave,sinusoidal wave, and waves with desired harmonic components to mimicwhite noise such as is indicative of naturally-occurring baroreflexstimulation.

FIG. 8 illustrates a system 828 including a programmer 830, animplantable neural stimulator (NS) device 835 and an implantable cardiacrhythm management (CRM) device 836, according to various embodiments ofthe present subject matter. Various aspects involve a method forcommunicating between an NS device and a CRM device or other cardiacstimulator. In various embodiments, this communication allows one of thedevices 835 or 836 to deliver more appropriate therapy (i.e. moreappropriate NS therapy or CRM therapy) based on data received from theother device. Thus, for example, the CRM device can detect myocardialcapture by a neural stimulation pulse. Some embodiments provideon-demand communications. In various embodiments, this communicationallows each of the devices 835 and 836 to deliver more appropriatetherapy (i.e. more appropriate NS therapy and CRM therapy) based on datareceived from the other device. The illustrated NS device and the CRMdevice are capable of wirelessly communicating with each other, and theprogrammer is capable of wirelessly communicating with at least one ofthe NS and the CRM devices. For example, various embodiments usetelemetry coils to wirelessly communicate data and instructions to eachother. In other embodiments, communication of data and/or energy is byultrasonic means.

In some embodiments, the NS device stimulates the baroreflex to provideNS therapy, and some device embodiments sense ANS activity directly orusing surrogate parameters, such as respiration and blood pressure,indicative of ANS activity. The CRM device includes cardiac stimulationcapabilities, such as pacing and defibrillating capabilities. Ratherthan providing wireless communication between the NS and CRM devices,various embodiments provide a communication cable or wire, such as anintravenously-fed lead, for use to communicate between the NS device andthe CRM device.

FIG. 9 illustrates an implantable neural stimulator (NS) device 935 suchas shown at 835 in the system of FIG. 8, according to variousembodiments of the present subject matter. FIG. 10 illustrates animplantable cardiac rhythm management (CRM) device 1036 such as shown at836 in the system of FIG. 8, according to various embodiments of thepresent subject matter. Various embodiments of the NS and CRM devicesinclude wireless transceivers 937 and 1037, respectively, to wirelesslycommunicate with each other. Various embodiments of the NS and CRMdevices include a telemetry coil or ultrasonic transducer to wirelesslycommunicate with each other.

According to various embodiments, for example, the NS device is equippedwith a telemetry coil, allowing data to be exchanged between it and theCRM device, allowing the NS device to modify therapy based onelectrophysiological parameters such as heart rate, minute ventilation,atrial activation, ventricular activation, and cardiac events. Inaddition, some CRM device embodiments modify therapy based on datareceived from the NS device.

Some NS device embodiments are able to be implanted in patients withexisting CRM devices, such that the functionality of the NS device isenhanced by receiving physiological data that is acquired by the CRMdevice. For example, the CRM device is capable of detecting myocardialcapture in response to the neural stimulation signal. The functionalityof two or more implanted devices is enhanced by providing communicationcapabilities between or among the implanted devices. In variousembodiments, the functionality is further enhanced by designing thedevices to wirelessly communicate with each other.

FIG. 11 illustrates a system to automatically adjust a neuralstimulation signal to achieve a desired result and avoid an undesiredresult, according to various embodiments. The illustrated neuralstimulator 1138 includes a pulse generator 1139 to provide a neuralstimulation signal as part of a neural stimulation therapy, a modulator1140 to change or modulate parameter(s) of the neural stimulationsignal, and a desired response feedback monitor 1141 to provide adesired response feedback. Various stimulator embodiments areimplantable. The nervous system is generally illustrated at 1142. Thedevice 1138 uses appropriate electrode(s) 1143 to provide desired neuralstimulation and sensor(s) 1144 to sense a parameter that is quicklyaffected by the neural stimulation. Examples of such parameters includeheart rate, blood pressure, and respiration. Other parameter(s) andother surrogate parameters that have a quick and predictable responseindicative of the overall response of the parasympathetic nervous systemto the neural stimulation. The sensor(s) and electrode(s) can beintegrated on a single lead or can use multiple leads. Additionally,various system embodiments implement the functions illustrated in FIG.11 using an implantable neural stimulator capable of communicating witha distinct or integrated implantable cardiac rhythm management device.The illustrated device 1138 also includes an undesired response feedbackmonitor 1145 to provide an undesired response feedback.

The illustrated undesired response feedback monitor 1145 includes meansfor sensing or otherwise detecting an undesired result of the neuralstimulation therapy. Various embodiments monitor cardiac activity formyocardial capture, various embodiments monitor a smooth musclecontraction for capture of the smooth muscle, and various embodimentsmonitor neural activity of a non-targeted nerve or a surrogate parameterassociated with the non-targeted nerve. The illustrated desired feedbackmonitor 1141 monitors the parameter during a time with stimulation (orimmediately after stimulation) to provide a first feedback signal 1146indicative of a parameter value corresponding to a time with stimulationand during a time without stimulation to provide a second feedbacksignal 1147 indicative of a parameter value corresponding to a timewithout stimulation. The signals 1146 and 1147 are illustrated asseparate lines. These signals can be sent over different signal paths orover the same signal path. A comparator 1148 receives the first andsecond feedback signals 1146 and 1147 and determines a detected changein the parameter value based on these signals. Additionally, thecomparator compares the detected change with a desired change, asgenerally represented at 1149. In various embodiments, the desiredchange is a programmable parameter. Various embodiments program thedesired change as a percent change (e.g. 5% to 10% reduction in heartrate from a heart rate during a time without stimulation to a heart rateduring a time with stimulation). Various embodiments the desired changeas a change in quantitative value (e.g. 5 bpm to 10 bpm reduction inheart rate from a heart rate during a time without stimulation to aheart rate during a time with stimulation). A comparison of the detectedchange (based on signals 1146 and 1147) and the desired change (based onvalue 1149) provide a comparison result 1150, which is used toappropriately control the modulator to adjust the applied neuralstimulation. Various modulator embodiments change an amplitude of astimulation signal used to provide the neural stimulation. Variousmodulator embodiments change a frequency of a stimulation signal used toprovide the neural stimulation. Various modulator embodiments change aburst frequency of a stimulation signal used to provide the neuralstimulation. Various modulator embodiments change a pulse width of astimulation signal used to provide the neural stimulation. Variousmodulator embodiments change a duty cycle of a stimulation signal usedto provide the neural stimulation. Various modulator embodiments changea morphology cycle of a stimulation signal used to provide the neuralstimulation. Morphology examples includes sinusoidal, square, triangularand “white noise” with harmonic components that provide a signal thatmimics neural activity. Various modulator embodiments change variouscombinations of two or more of these stimulation signal characteristics.

The illustrated system is useful in extended therapy applications.Examples of extended therapy applications involve applying stimulationto prevent remodeling of cardiac tissue and to reverse remodel cardiactissue in cardiovascular disease. However, the present subject matterapplies to other extended therapies. Neural stimulation in one of thesetherapies can be applied for a portion (5 to 10 seconds) of each minute,for example. Over the course of days, weeks, months and years, theefficacy of a given neural stimulation with respect to a desiredresponse of a parasympathetic nervous system can vary for a number ofreasons, such as nerve adaptation, tissue encapsulation, fibrosis,impedance changes, and the like. Additionally, systemic adaptation (i.e.an adaptation that results in attenuation of the heart rate effect inthe absence of changes in the electrode or nerve) can adversely affectthe efficacy of a given neural stimulation over time. The illustratedsystem monitors a parameter that has a quick and predictable response toan applied neural stimulation, and uses the monitored parameter toappropriately change the neural stimulation signal to result in adesired stimulation of the parasympathetic nervous system.

Programmed Therapy Applications

The devices and systems illustrated above perform neural stimulationtherapy applications/processes. These processes can be performed by aprocessor executing computer-readable instructions embedded in memory,for example. These therapies include a number of applications, whichhave various processes and functions, some of which are identified anddiscussed below. Embodiments of a neural stimulation application includeavoidance of undesired results from a neural stimulation therapy; andembodiments of a neural stimulation application include both avoidanceof undesired results from a neural stimulation therapy, and insurance ofa desired result from the neural stimulation therapy. The processes andfunctions of these therapies are not necessarily mutually exclusive, assome embodiments of the present subject matter include combinations oftwo or more of the below-identified processes and functions. Somefeatures of these process are illustrated by functional blocks in thesystems described and illustrated previously.

FIG. 12 illustrates an application 1251, illustrated as functional blockdiagrams for a system, to modulate neural stimulation, according tovarious embodiments of the present subject matter. The illustratedsystem includes a neural stimulator 1252, such as stimulator tostimulate baroreceptors in and around the pulmonary artery. Thebaroreflex stimulator can be included in a stand-alone NS device or as aNS component in an integrated NS/CRM device, for example. Theillustrated stimulator 1252 includes a modulator 1253 for use toselectively increase and decrease the applied neural stimulation.According to various embodiments, the modulator includes any one of thefollowing modules: a module to change the amplitude of the stimulationpulse; a module to change the frequency of the stimulation pulse; amodule to change the burst frequency of the stimulation pulse, a moduleto change the duty cycle of the stimulation pulse, and a module tochange the morphology of the stimulation signal. According to variousembodiments, the modulator includes functions for the variouscombinations of two or more of the modules.

The stimulation can be applied to an afferent nerve trunk such as thevagal nerve using a cuff electrode or an intravascularly-fed leadpositioned proximate to the nerve trunk. The stimulation can be appliedto baroreceptor sites such are located in the pulmonary artery, aorticarch, and carotid sinus, for example, using intravenously-fed leads. Thestimulation can be applied to baroreceptor sites located in cardiac fatpads using intravenously-fed leads or by screwing electrodes into thefat pads.

Embodiments include one or more monitors to detect an undesired result,and in some embodiments, a desired result along with an undesiredresult. Undesired results include myocardial capture 1254, capture ofsmooth muscle 1255, and depolarization of a non-targeted nerve, whichcan be detected by a neural traffic monitor 1256 and/or a physiologymonitor 1257 to detect heart rate, tidal volume, minute ventilationand/or blood pressure. The modulator 1253 is responsive to at least oneof the monitors 1254, 1255, 1256 and 1257 to appropriately adjustparameter(s) of the neural stimulation signal to avoid undesired resultsfrom inappropriate stimulation, and in some embodiments, insure desiredresults from stimulation of the targeted nerve(s).

FIG. 13 illustrates a neural stimulation application, according tovarious embodiments. At 1358, neural stimulation is applied to targetednerve(s). At 1359, it is determined whether the neural stimulationresults in an undesired response. For example, one embodiment determineswhether the neural stimulation results in an undesired myocardialcapture. If the neural stimulation results in an undesired response, atleast one neural stimulator parameter is adjusted at 1360. If the neuralstimulation does not result in a desired response, some embodimentsdetermine, at 1361, whether the neural stimulation provides a desiredresponse by eliciting depolarization of targeted nerve(s). If the neuralstimulation does not depolarize the targeted nerve(s), at least oneneural stimulator parameter is adjusted at 1362. Other embodimentsperform the illustrated functions in a different order.

FIG. 14 illustrates a neural stimulation application, according tovarious embodiments. At 1458, neural stimulation is applied to targetednerve(s). At 1459, it is determined whether the neural stimulationresults in an undesired response. For example, one embodiment determineswhether the neural stimulation results in an undesired myocardialcapture. If the neural stimulation does not result in a desiredresponse, the illustrated embodiments determine, at 1461, whether theneural stimulation provides a desired response by elicitingdepolarization of targeted nerve(s). If the neural stimulationdepolarizes the targeted nerve(s), the successful neural stimulationsignal parameter(s) are used to the NS therapy, as illustrated at 1462.

If an undesired response from the stimulation is detected at 1459 or adesired response from the stimulation is not detected at 1461, theprocess proceeds to change an amplitude of the neural stimulationsignal, then change a frequency of the neural stimulation signal if theamplitude change was not effective, and then change another parameter ofthe neural stimulation signal if the changes to the amplitude andfrequency were not effective. Thus, in the illustrated embodiment, forexample, the process proceeds to 1463 to determine if an amplitudechange counter is exceeded. If the counter is not exceeded, the processcontinues to change an amplitude (decrease if detected undesiredresponse and increase if did not detect desired response) at 1464,increment the amplifier change counter at 1465, and continue to applythe NS therapy at 1458.

If, at 1463, it is determined that that the amplitude change count isexceeded, the process proceeds to determine if a frequency changecounter is exceeded at 1466. If the counter is not exceeded, thefrequency is changed at 1467, the frequency counter is incremented at1468, and NS therapy continues at 1458. Some embodiments clear theamplifier change counter at 1469, such that the amplitude will bechanged again for the new frequency before changing the frequency again.

If, at 1466, it is determined that the frequency change count isexceeded, the process proceeds to 1470 to determine if an other signalparameter change is exceeded. If the counter is not exceeded, theparameter is changed at 1471, the other parameter counter is incrementedat 1472, and NS therapy continues at 1458. Some embodiments clear theamplitude and/or frequency counters at 1473 to modulate the amplitudeand/or frequency again before modulating the other parameter. If, at1470, the other signal parameter change counter is exceeded, a timeoutmessage 1474 is provided. In response to a timeout message, the positionof the neural stimulation leads can be adjusted. The process cancontinue to modulate other parameters. Examples of other parametersinclude pulse width, burst frequency, duty cycle and morphology.

FIG. 15 is a graphical illustration of the relationship between a changein blood pressure and a rate of a stimulation signal. The figureillustrates that the frequency of the stimulation signal significantlyaffects the decrease in blood pressure, which is a surrogate baroreflexparameter indicating the inhibition of SNA. Thus, the figure illustratesthat the intensity of the neural stimulation depends on the frequency ofthe neural stimulation figure. The figure illustrates that a maximumdecrease in blood pressure occurs at a stimulation frequency within arange from about 64 to about 256 Hz, and occurs approximately at 128 Hz.

Various embodiments of the present subject matter modulate the frequencyof the stimulation signal. Various embodiments stimulate with afrequency between approximately 8 Hz and approximately 512 Hz, orvarious ranges within this range such as approximately 16 Hz toapproximately 128 Hz, approximately 32 Hz to approximately 128 Hz, forexample. Various embodiments start with a predetermined frequencyestimated to provide good neural stimulation, and then graduallyincrease and decrease the frequency from the predetermined frequency inan effort to improve the neural stimulation intensity to the targetednerve(s).

FIG. 16 illustrates a method to detect myocardial capture, according tovarious embodiments. Such a method can be used at 1359 and 1459 in FIGS.13 and 14, for example. At 1675, a neural stimulation burst is appliedas part of a neural stimulation therapy using a neural stimulationelectrode proximate to the heart. At 1676, the device waits for ablanking period. At 1677, after the blanking period, the myocardialactivation is sensed using the neural stimulation electrode.

FIG. 17 illustrates a method to detect myocardial capture, according tovarious embodiments. Such a method can be used at 1359 and 1459 in FIGS.13 and 14, for example. At 1778, a neural stimulation burst is appliedas part of a neural stimulation therapy using a neural stimulationelectrode proximate to the heart. At 1779, a myocardial activation issensed using the neural stimulation electrode and another electrode.

FIG. 18 illustrates a method to detect myocardial capture, according tovarious embodiments. Such a method can be used at 1359 and 1459 in FIGS.13 and 14, for example. This embodiment is useful if the neuralstimulation therapy includes longer stimulation bursts that depolarizethe myocardium. At 1880, a neural stimulation therapy is provided. Theneural stimulation therapy is interrupted at 1881 and a test stimulationburst is provided. At 1882, myocardial activation is sensed, and theneural stimulation therapy continues at 1883.

One of ordinary skill in the art will understand that, the modules andother circuitry shown and described herein can be implemented usingsoftware, hardware, and combinations of software and hardware. As such,the term module is intended to encompass software implementations,hardware implementations, and software and hardware implementations.

The methods illustrated in this disclosure are not intended to beexclusive of other methods within the scope of the present subjectmatter. Those of ordinary skill in the art will understand, upon readingand comprehending this disclosure, other methods within the scope of thepresent subject matter. The above-identified embodiments, and portionsof the illustrated embodiments, are not necessarily mutually exclusive.These embodiments, or portions thereof, can be combined. For example,various embodiments combine two or more of the illustrated processes.

In various embodiments, the methods provided above are implemented as acomputer data signal embodied in a carrier wave or propagated signal,that represents a sequence of instructions which, when executed by aprocessor cause the processor to perform the respective method. Invarious embodiments, methods provided above are implemented as a set ofinstructions contained on a computer-accessible medium capable ofdirecting a processor to perform the respective method. In variousembodiments, the medium is a magnetic medium, an electronic medium, oran optical medium.

Although specific embodiments have been illustrated and describedherein, it will be appreciated by those of ordinary skill in the artthat any arrangement which is calculated to achieve the same purpose maybe substituted for the specific embodiment shown. This application isintended to cover adaptations or variations of the present subjectmatter. It is to be understood that the above description is intended tobe illustrative, and not restrictive. Combinations of the aboveembodiments as well as combinations of portions of the above embodimentsin other embodiments will be apparent to those of skill in the art uponreviewing the above description. The scope of the present subject mattershould be determined with reference to the appended claims, along withthe full scope of equivalents to which such claims are entitled.

1. (canceled)
 2. An implantable device, comprising: a neural stimulatorconfigured to deliver a programmed intermittent neural stimulationtherapy for an extended therapy application, the programmed intermittentneural stimulation therapy including a programmed series of stimulationON times and stimulation OFF times, each programmed stimulation ON timefor the programmed intermittent neural stimulation therapy including aprogrammed neural stimulation burst of neural stimulation pulses, theneural stimulator including: a pulse generator configured to generatethe neural stimulation pulses for the neural stimulation therapy; and amodulator to adjust the neural stimulation therapy; a monitor to monitorat least one parameter during stimulation ON times and duringstimulation OFF times of the programmed intermittent neural stimulationtherapy, the at least one parameter being affected by depolarization ofa non-targeted nerve; a controller operably connected to the monitor,and configured to detect a change for the at least one parameter betweenthe stimulation ON and stimulation OFF times and provide a therapycontrol signal to the modulator to avoid the depolarization of thenon-targeted nerve.
 3. The implantable device of claim 2, wherein themonitor includes a monitor of nerve traffic affected by depolarizationof the non-targeted nerve.
 4. The implantable device of claim 2, whereinthe modulator is configured to adjust an amplitude of the neuralstimulation pulses to avoid the depolarization of the non-targetednerve.
 5. The implantable device of claim 2, wherein the modulator isconfigured to adjust a frequency of the neural stimulation pulses toavoid the depolarization of the non-targeted nerve.
 6. The implantabledevice of claim 2, wherein the modulator is configured to adjust a burstfrequency of the neural stimulation pulses to avoid the depolarizationof the non-targeted nerve.
 7. The implantable device of claim 2, whereinthe modulator is configured to adjust a pulse width of the neuralstimulation pulses to avoid the depolarization of the non-targetednerve.
 8. The implantable device of claim 2, wherein the modulator isconfigured to adjust a duty cycle of the neural stimulation pulses toavoid the depolarization of the non-targeted nerve.
 9. The implantabledevice of claim 2, wherein the intermittent neural stimulation therapycauses at least one physiological response including a change in the atleast one physiological response when transitioning from stimulation ONtimes to stimulation OFF times or when transitioning from stimulationOFF times to stimulation ON times, and the modulator is configured tomaintain a predefined change in the monitored at least one physiologicalresponse when transitioning from stimulation ON times to stimulation OFFtimes or when transitioning from stimulation OFF times to stimulation ONtimes.
 10. A method, comprising: delivering a programmed intermittentneural stimulation therapy for an extended therapy application, theprogrammed intermittent neural stimulation therapy including aprogrammed series of stimulation ON times and stimulation OFF times,each programmed stimulation ON time for the programmed intermittentneural stimulation therapy including a programmed neural stimulationburst of neural stimulation pulses; monitoring at least one parameterduring stimulation ON times and during stimulation OFF times of theprogrammed intermittent neural stimulation therapy, the at least oneparameter being affected by depolarization of a non-targeted nerve;detecting a change for the at least one parameter between thestimulation ON and stimulation OFF times; and providing a therapycontrol signal to the modulator to avoid the depolarization of thenon-targeted nerve.
 11. The method of claim 10, wherein the monitoringincludes monitoring of nerve traffic affected by depolarization of thenon-targeted nerve.
 12. The method of claim 10, wherein the providingthe therapy control signal includes providing a signal to adjust anamplitude of the neural stimulation pulses to avoid the depolarizationof the non-targeted nerve.
 13. The method of claim 10, wherein theproviding the therapy control signal includes providing a signal toadjust a frequency of the neural stimulation pulses to avoid thedepolarization of the non-targeted nerve.
 14. The method of claim 10,wherein the providing the therapy control signal includes providing asignal to adjust a burst frequency of the neural stimulation pulses toavoid the depolarization of the non-targeted nerve.
 15. The method ofclaim 10, wherein the providing the therapy control signal includesproviding a signal to adjust a pulse width of the neural stimulationpulses to avoid the depolarization of the non-targeted nerve.
 16. Themethod of claim 10, wherein the providing the therapy control signalincludes providing a signal to adjust a duty cycle of the neuralstimulation pulses to avoid the depolarization of the non-targetednerve.
 17. The method of claim 10, wherein the intermittent neuralstimulation therapy causes at least one physiological response includinga change in the at least one physiological response when transitioningfrom stimulation ON times to stimulation OFF times or when transitioningfrom stimulation OFF times to stimulation ON times, and the modulator isconfigured to maintain a predefined change in the monitored at least onephysiological response when transitioning from stimulation ON times tostimulation OFF times or when transitioning from stimulation OFF timesto stimulation ON times.
 18. A non-transitory machine-readable mediumincluding instructions, which when executed by a machine, cause themachine to: deliver a programmed intermittent neural stimulation therapyfor an extended therapy application, the programmed intermittent neuralstimulation therapy including a programmed series of stimulation ONtimes and stimulation OFF times, each programmed stimulation ON time forthe programmed intermittent neural stimulation therapy including aprogrammed neural stimulation burst of neural stimulation pulses;monitor at least one parameter during stimulation ON times and duringstimulation OFF times of the programmed intermittent neural stimulationtherapy, the at least one parameter being affected by depolarization ofa non-targeted nerve; detect a change for the at least one parameterbetween the stimulation ON and stimulation OFF times; and provide atherapy control signal to the modulator to avoid the depolarization ofthe non-targeted nerve.
 19. The non-transitory machine-readable mediumof claim 18, wherein the at least one parameter is monitored duringstimulation ON times and during stimulation OFF times of the programmedintermittent neural stimulation therapy.
 20. The non-transitorymachine-readable medium of claim 18, wherein the therapy control signalincludes a signal to adjust at least one of an amplitude, a frequency, aburst frequency, a pulse width or a duty cycle of the neural stimulationpulses to avoid the depolarization of the non-targeted nerve.
 21. Thenon-transitory machine-readable medium of claim 18, wherein theintermittent neural stimulation therapy causes at least onephysiological response including a change in the at least onephysiological response when transitioning from stimulation ON times tostimulation OFF times or when transitioning from stimulation OFF timesto stimulation ON times, and the instructions cause the machine tomaintain a predefined change in the monitored at least one physiologicalresponse when transitioning from stimulation ON times to stimulation OFFtimes or when transitioning from stimulation OFF times to stimulation ONtimes.